Substituted carbamothioic amine-1-carbothioic thioanhydrides as novel trichomonicidal fungicides: Design, synthesis, and biology

Eur J Med Chem. 2018 Jan 1:143:632-645. doi: 10.1016/j.ejmech.2017.11.060.

Dhanaraju Mandalapu ¹, Bhavana Kushwaha ², Sonal Gupta ³, Shagun Krishna ⁴, Nidhi Srivastava ¹, Mahendra Shukla ⁵, Pratiksha Singh ⁶, Bhavana S Chauhan ⁷, Ravi Goyani ⁸, Jagdamba P Maikhuri ², Koneni V Sashidhara ¹, Brijesh Kumar ⁹, Renu Tripathi ⁷, Praveen K Shukla ⁶, Mohammad I Siddiqi ⁴, Jawahar Lal ⁵, Gopal Gupta ², Vishnu L Sharma ¹⁰

Affiliations

1 Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.
2 Endocrinology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.
3 Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
4 Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.
5 Pharmacokinetic & Metabolism Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.
6 Microbiology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.
7 Parasitology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.
8 Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229 010, India.
9 Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India.
10 Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: vl_sharma@cdri.res.in.

PMID: 29216562 DOI: 10.1016/j.ejmech.2017.11.060

Abstract

Sexually transmitted diseases like trichomoniasis along with opportunistic Fungal infections like candidiasis are major global health burden in female reproductive health. In this context a novel non-nitroimidazole class of substituted carbamothioic amine-1-carbothioic thioanhydride series was designed, synthesized, evaluated for trichomonacidal and fungicidal activities, and was found to be more active than the standard drug Metronidazole (MTZ). Compounds were trichomonicidal in the MIC ranges of 4.77-294.1 μM and 32.46-735.20 μM against MTZ-susceptible and -resistant strains, respectively. Further, compounds inhibited the growth of at least two out of ten Fungal strains tested at MIC of 7.50-240.38 μM. The most active compound (20) of this series was 3.8 and 9.5 fold more active than the MTZ against the two Trichomonas strains tested. Compound 20 also significantly inhibited the sulfhydryl groups present over Trichomonas vaginalis and was found to be more active than the MTZ in vivo. Further, a docking analysis carried out with cysteine proteases supported their thiol inhibiting ability and preliminary pharmacokinetic study has shown good distribution and systemic clearance.

Keywords

Candidiasis; Carbamothioic; Thioanhydrides; Thiol inhibition; Trichomoniasis.

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